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Background: Recent studies have emphasized the importance of the biological processes of different forms of cell death in tumor heterogeneity and anti-tumor immunity. Nonetheless, the relationship between cuproptosis and lung adenocarcinoma (LUAD) remains largely unexplored. Methods: Data for 793 LUAD samples and 59 normal lung tissues obtained from TCGA-LUAD cohort GEO datasets were used in this study. A total of 165 LUAD tissue samples and paired normal lung tissue samples obtained from our hospital were used to verify the prognostic value of dihydrolipoamide S-acetyltransferase (DLAT) and dihydrolipoamide branched chain transacylase E2 (DBT) for LUAD. The cuproptosis-related molecular patterns of LUAD were identified using consensus molecular clustering. Recursive feature elimination with random forest and a tenfold cross-validation method was applied to construct the cuproptosis score (CPS) for LUAD. Results: Bioinformatic and immunohistochemistry (IHC) analyses revealed that 13 core genes of cuproptosis were all significantly elevated in LUAD tissues, among which DBT and DLAT were associated with poor prognosis (DLAT, HR = 6.103; DBT, HR = 4.985). Based on the expression pattern of the 13 genes, two distinct cuproptosis-related patterns have been observed in LUAD: cluster 2 which has a relatively higher level of cuproptosis was characterized by immunological ignorance; conversely, cluster 1 which has a relatively lower level of cuproptosis is characterized by TILs infiltration and anti-tumor response. Finally, a scoring scheme termed the CPS was established to quantify the cuproptosis-related pattern and predict the prognosis and the response to immune checkpoint blockers of each individual patient with LUAD. Conclusion: Cuproptosis was found to influence tumor microenvironment (TME) characteristics and heterogeneity in LUAD. Patients with a lower CPS had a relatively better prognosis, more abundant immune infiltration in the TME, and an enhanced response to immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Background: Ephrin receptors (Eph) and their ligands, called ephrins, function in various disease processes. However, the expression level and prognostic value of Eph/ephrins in lung adenocarcinoma (LUAD) are still unclear. Methods: The Oncomine and GEPIA databases were used to explore the differential expression of Eph/ephrins in LUAD. Kaplan–Meier plotter was selected to explore the prognostic value of Eph/ephrins. The cBioPortal database was used to analyze the genetic variation of the EFNA3 gene. Immunohistochemistry was used to analyze the expression level and clinical value of ephrin-A3 protein in clinical LUAD tissue. Weighted coexpression network analysis (WGCNA) and gene set enrichment analysis (GSEA) identified the potential regulatory mechanism of EFNA3. CCK-8 assays and colony-forming experiments were used to investigate whether EFNA3 can regulate cell proliferation ability in LUAD. Analysis of lactate, ATP, and glucose uptake levels was used to explore the effect of EFNA3 on glycolysis ability. In addition, we investigated the relationship between EFNA3 and tumor infiltrating immune cells (TIICs). Finally, the potential immunotherapy response prediction value of EFNA3 was also explored. Results: In this study, we found that EFNA3 expression was significantly correlated with both overall survival (OS) and progression-free survival (PFS) in LUAD patients based on a comprehensive analysis of the Eph/Ephrin family. Next, the expression of the EFNA3 protein was increased in LUAD tissues and was designated an independent prognostic risk factor. Mechanistically, EFNA3 may be involved in nuclear division, synaptic function, and ion channel activity-related pathways. In vitro experiments confirmed the role of EFNA3 in promoting LUAD cells and showed that it could regulate glycolytic capacity. Moreover, EFNA3 was negatively associated with immunity, stromal infiltration, and several TIICs. Finally, EFNA3 was found to be positively related to multiple immunotherapy biomarkers. Conclusions: In conclusion, increased EFNA3 in LUAD patients predicted worse clinical prognosis, promoted LUAD cell proliferation and glycolysis ability, and was related to immunotherapy response. [ABSTRACT FROM AUTHOR]

Oxidative stress and chronic inflammation play key roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). Astaxanthin (AXT) is a keto-carotenoid with a variety of biological functions, including antioxidant and anti-inflammatory effects This study aimed to explore the protective role and underlying mechanism of AXT in the pathogenesis of COPD. In this study, we found AXT alleviated pulmonary emphysema in a CS-exposed mouse model and regulated the expression of MMP-9/TIMP-1. And, AXT attenuates CSE-induced small airway fibrosis. Meanwhile, AXT inhibited Nrf2-modulated oxidative stress and the p65 NF-κB-regulated inflammatory pathway in both the mouse model and CSE-treated HBE cells. Mechanistically, AXT could directly bind to SIRT1 (the binding energy of the complex was −8.8 kcal/mol) and regulate the deacetylation activity of SIRT1. Finally, by activating SIRT1 deacetylation, AXT deacetylated Nrf2 and contributed to its action of reducing oxidative stress by generating antioxidant enzymes, and inhibiting p65 NF-κB transcriptional activity to suppress the inflammatory response. Our results show that treatment with AXT significantly reverses the oxidative stress and inflammation induced by cigarette smoke both in vivo and in vitro in a sirtuin 1-dependent manner. [Display omitted] • Astaxanthin alleviated cigarette smoke extract-induced pulmonary emphysema and small airway fibrosis. • Astaxanthin inhibited Nrf2-modulated oxidative stress and the NF-κB-regulated inflammatory pathway. • Astaxanthin directly binds and activates SIRT1. • AXT upregulates the deacetylation levels of Nrf2 and NF-κB p65 exert antioxidant and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Recent studies have emphasized the close relationship between macrophages and tumor immunity, and the prognosis of lung adenocarcinoma (LUAD) patients is intimately linked to this. Nonetheless, the prognostic signature and classification of different immune patterns in LUAD patients based on the macrophages is largely unexplored. Two sc-RNAseq datasets of LUAD patients were collected and reprocessed. The differentially expressed genes (DEGs) related to macrophages between LUAD tissues and normal lung tissues were then identified. Based upon the above genes, three distinct immune patterns in the TCGA-LUAD cohort were identified. The ssGSEA and CIBERSORT were applied for immune profiling and characterization of different subtypes. A four-gene prognostic signature for LUAD patients was established based on the DEGs between the subtypes using stepwise multi-Cox regression. TCGA-LUAD cohort was used as training set. Five GEO-LUAD datasets and an independent cohort containing 112 LUAD samples were used for validation. TIDE (tumor immune dysfunction and exclusion) and drug sensitivity analyses were also performed. Macrophage-related differentially expressed genes were found out using the publicly available scRNA-seq data of LUAD. Three different immune patterns which were proved to have distinct immune infiltration characteristics in the TCGA-LUAD cohort were recognized based on the above macrophage-related genes. Thereafter, 174 DEGs among the above three different immune patterns were figured out; on the basis of this, a four-gene prognostic signature was constructed. This signature distinguished the prognosis of LUAD patients well in various GSE datasets as well as our independent cohort. Further analyses revealed that patients which had a higher risk score also accompanied with a lower immune infiltration level and a worse response to several immunotherapy biomarkers. This study highlighted that macrophage were significantly associated with TME diversity and complexity. The four-gene prognostic signature could be used for predicting outcomes and immune landscapes for patients with LUAD. [Display omitted] • Depicting the LUAD landscape and acquiring macrophage-related differentially expressed genes from scRNAseq data of LUAD. • Identifying and depicting 3 distinct LUAD subtypes with distinct immune landscapes which were termed as "immune-infiltrated phenotype", "immune-excluded phenotype" and "immune-desert phenotype". • Establishment of a four-gene prognostic model for LUAD patients and validation of the signature using publicly attainable LUAD cohorts and an independent cohort containing 112 LUAD samples. [ABSTRACT FROM AUTHOR]

Introduction: Transbronchial lung cryobiopsy (TBLC) is increasingly used to diagnose interstitial lung disease (ILD). The 1.1-mm cryoprobe has recently been available in clinical practice. The diagnostic yield and safety of TBLC using a 1.1-mm cryoprobe need to be confirmed.A prospective, randomized controlled trial was conducted in patients with suspected ILD and randomly assigned to 1.1-mm and 1.9-mm cryoprobe groups. The primary outcome was the diagnostic yield of multidisciplinary discussion. Secondary outcomes were sample quality and incidence of complications. The tension and stress effects during TBLC onto the target lobe caused by 1.1-mm and 1.9-mm cryoprobes were also evaluated using finite element analysis.A total of 224 patients were enrolled. No significant differences were observed in the diagnostic yield (80.4% vs. 79.5%, p = 0.845) and sample quality scores (5.73 ± 0.64 vs. 5.66 ± 0.77; p = 0.324) between the 1.9-mm cryoprobe group and 1.1-mm cryoprobe group. The average surface areas of samples in 1.1-mm cryoprobe group were smaller, while no difference in sample weights was observed. A decreased incidence of moderate bleeding was found in the 1.1-mm cryoprobe group (17.0% vs. 6.2%, p = 0.027), while there was no difference in the incidence of the pneumothorax, there was a trend to higher rate of pneumothorax in 1.1-mm group. In finite element analysis, the 1.1-mm cryoprobe required the largest tension and produced the largest stress.Compared with a 1.9-mm cryoprobe, there was no difference in specimen quality or diagnostic rate but smaller sample size with a 1.1-mm cryoprobe. There was a decreased risk of moderate bleeding, but a trend towards increased risk for pneumothorax with 1.1-mm cryoprobe.Trail Registration: Clinicaltrials.gov identifier NCT04047667; registered August 4, 2019.Methods: Transbronchial lung cryobiopsy (TBLC) is increasingly used to diagnose interstitial lung disease (ILD). The 1.1-mm cryoprobe has recently been available in clinical practice. The diagnostic yield and safety of TBLC using a 1.1-mm cryoprobe need to be confirmed.A prospective, randomized controlled trial was conducted in patients with suspected ILD and randomly assigned to 1.1-mm and 1.9-mm cryoprobe groups. The primary outcome was the diagnostic yield of multidisciplinary discussion. Secondary outcomes were sample quality and incidence of complications. The tension and stress effects during TBLC onto the target lobe caused by 1.1-mm and 1.9-mm cryoprobes were also evaluated using finite element analysis.A total of 224 patients were enrolled. No significant differences were observed in the diagnostic yield (80.4% vs. 79.5%, p = 0.845) and sample quality scores (5.73 ± 0.64 vs. 5.66 ± 0.77; p = 0.324) between the 1.9-mm cryoprobe group and 1.1-mm cryoprobe group. The average surface areas of samples in 1.1-mm cryoprobe group were smaller, while no difference in sample weights was observed. A decreased incidence of moderate bleeding was found in the 1.1-mm cryoprobe group (17.0% vs. 6.2%, p = 0.027), while there was no difference in the incidence of the pneumothorax, there was a trend to higher rate of pneumothorax in 1.1-mm group. In finite element analysis, the 1.1-mm cryoprobe required the largest tension and produced the largest stress.Compared with a 1.9-mm cryoprobe, there was no difference in specimen quality or diagnostic rate but smaller sample size with a 1.1-mm cryoprobe. There was a decreased risk of moderate bleeding, but a trend towards increased risk for pneumothorax with 1.1-mm cryoprobe.Trail Registration: Clinicaltrials.gov identifier NCT04047667; registered August 4, 2019.Results: Transbronchial lung cryobiopsy (TBLC) is increasingly used to diagnose interstitial lung disease (ILD). The 1.1-mm cryoprobe has recently been available in clinical practice. The diagnostic yield and safety of TBLC using a 1.1-mm cryoprobe need to be confirmed.A prospective, randomized controlled trial was conducted in patients with suspected ILD and randomly assigned to 1.1-mm and 1.9-mm cryoprobe groups. The primary outcome was the diagnostic yield of multidisciplinary discussion. Secondary outcomes were sample quality and incidence of complications. The tension and stress effects during TBLC onto the target lobe caused by 1.1-mm and 1.9-mm cryoprobes were also evaluated using finite element analysis.A total of 224 patients were enrolled. No significant differences were observed in the diagnostic yield (80.4% vs. 79.5%, p = 0.845) and sample quality scores (5.73 ± 0.64 vs. 5.66 ± 0.77; p = 0.324) between the 1.9-mm cryoprobe group and 1.1-mm cryoprobe group. The average surface areas of samples in 1.1-mm cryoprobe group were smaller, while no difference in sample weights was observed. A decreased incidence of moderate bleeding was found in the 1.1-mm cryoprobe group (17.0% vs. 6.2%, p = 0.027), while there was no difference in the incidence of the pneumothorax, there was a trend to higher rate of pneumothorax in 1.1-mm group. In finite element analysis, the 1.1-mm cryoprobe required the largest tension and produced the largest stress.Compared with a 1.9-mm cryoprobe, there was no difference in specimen quality or diagnostic rate but smaller sample size with a 1.1-mm cryoprobe. There was a decreased risk of moderate bleeding, but a trend towards increased risk for pneumothorax with 1.1-mm cryoprobe.Trail Registration: Clinicaltrials.gov identifier NCT04047667; registered August 4, 2019.Conclusion: Transbronchial lung cryobiopsy (TBLC) is increasingly used to diagnose interstitial lung disease (ILD). The 1.1-mm cryoprobe has recently been available in clinical practice. The diagnostic yield and safety of TBLC using a 1.1-mm cryoprobe need to be confirmed.A prospective, randomized controlled trial was conducted in patients with suspected ILD and randomly assigned to 1.1-mm and 1.9-mm cryoprobe groups. The primary outcome was the diagnostic yield of multidisciplinary discussion. Secondary outcomes were sample quality and incidence of complications. The tension and stress effects during TBLC onto the target lobe caused by 1.1-mm and 1.9-mm cryoprobes were also evaluated using finite element analysis.A total of 224 patients were enrolled. No significant differences were observed in the diagnostic yield (80.4% vs. 79.5%, p = 0.845) and sample quality scores (5.73 ± 0.64 vs. 5.66 ± 0.77; p = 0.324) between the 1.9-mm cryoprobe group and 1.1-mm cryoprobe group. The average surface areas of samples in 1.1-mm cryoprobe group were smaller, while no difference in sample weights was observed. A decreased incidence of moderate bleeding was found in the 1.1-mm cryoprobe group (17.0% vs. 6.2%, p = 0.027), while there was no difference in the incidence of the pneumothorax, there was a trend to higher rate of pneumothorax in 1.1-mm group. In finite element analysis, the 1.1-mm cryoprobe required the largest tension and produced the largest stress.Compared with a 1.9-mm cryoprobe, there was no difference in specimen quality or diagnostic rate but smaller sample size with a 1.1-mm cryoprobe. There was a decreased risk of moderate bleeding, but a trend towards increased risk for pneumothorax with 1.1-mm cryoprobe.Trail Registration: Clinicaltrials.gov identifier NCT04047667; registered August 4, 2019. [ABSTRACT FROM AUTHOR]

Fixed airflow limitation (FAO), prevalent in patients with severe or difficult-to-treat asthma, is mainly caused by airway remodeling. Airway remodeling is initiated by inflammation and involves subsequent pathological changes. Glycyl- l -histidyl- l -lysine (GHK) is a matrikine with anti-inflammatory and antioxidant effects, naturally existing in human tissue. At present, the GHK level in human plasma and whether it is related to airway remodeling of asthma remain unclear. This study was conducted to determine how GHK is involved in airway remodeling in asthma. Our result showed that the plasma GHK levels of patients with asthma were significantly lower than those of age-matched healthy controls. In asthma patients, plasma GHK levels display a moderate correlation with FEF 25–75% , and patients with FAO had significantly lower GHK levels. Ovalbumin-induced mice of asthma model treated with PBS or GHK-Cu (a form of GHK with higher bioavailability) were used to evaluate the effect of exogenous GHK supplement on airway remodeling. GHK-Cu administration alleviated airway remodeling, as reflected by decreased peribronchial collagen deposition and airway mucus secretion, and suppressed epithelial-mesenchymal transition. The therapeutical effect related to decreased TGF-β1 level. Successively, network pharmacology and the validation data of experiments in vivo and vitro demonstrated that GHK-Cu decreased TGF-β1 level by increasing SIRT1 expression and activating SIRT1 deacetylation in airway epithelial cells, thereby alleviating airway remodeling. Collectively, decreased plasma GHK levels were related to FAO in asthma patients. Through the direct binding and activation of SIRT1, exogenous GHK-Cu administration alleviated airway remodeling in asthmatic mice. [Display omitted] • Decreased plasma GHK levels are related to fixed airflow limitation in asthma patients. • GHK-Cu protects against airway remodeling via direct binding and activation of SIRT1. • Exogenous GHK-Cu administration alleviates airway remodeling in asthmatic mice. [ABSTRACT FROM AUTHOR]